GlaxoSmithKline [R&D], New Frontier Science Park, Harlow CM19 5AW, UK.
J Pharm Biomed Anal. 2011 Jan 5;54(1):13-20. doi: 10.1016/j.jpba.2010.07.036. Epub 2010 Aug 6.
Pharmaceutical companies are progressively adopting and introducing the principles of Quality by Design with the main purpose of assurance and built-in quality throughout the whole manufacturing process. Within this framework, a Partial Least Square (PLS) model, based on Near Infrared (NIR) spectra and humidity determinations, was built in order to determine in-line the drying end point of a fluidized bed process. The in-process method was successfully validated following the principles described within The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH Q2 (r1) - Validation of Analytical Procedures: Text and Methodology. However, in some aspects, the cited guidelines were not appropriate to in-process methods developed and validated exclusively with in-line samples and implemented in dynamic systems, such as drying processes. In this work, a customized interpretation of guidelines has been adopted which provided the framework of evidence to support a validated application. The application has been submitted to the United States Food and Drug Administration (FDA) and The European Medicines Agency (EMA) during applications for grant of licences. Representatives from these Regulatory Authorities have specifically reviewed this novel application during on-site inspections, and have subsequently approved both the product and this application. Currently, the NIR method is implemented as a primary in-line method to control the drying end point in real-time (to below a control limit of not greater than 1.2% w/w) for commercial production batches of an approved, solid, oral-dose medicine. The implementation of this in-process method allows real-time control with benefits including a reduction in operation time and labour; sample handling and waste generation; and a reduced risk to product quality in further unit operations due to improved consistency of intermediate output at this stage. To date, this has achieved approximately 10% savings in energy efficiency and operational time for this part of the manufacturing process.
制药公司正在逐步采用和引入质量源于设计的原则，主要目的是在整个制造过程中保证和内置质量。在这个框架内，建立了一个基于近红外（NIR）光谱和湿度测定的偏最小二乘（PLS）模型，以便在线确定流化床工艺的干燥终点。该过程内方法是按照人用药品注册技术要求国际协调会议 - ICH Q2（r1）-分析程序验证：文本和方法中描述的原则成功验证的。然而，在某些方面，所引用的指南不适用于仅使用在线样品开发和验证的过程内方法，并且这些方法在动态系统（如干燥过程）中实施。在这项工作中，采用了定制的指南解释，为支持经过验证的应用提供了证据框架。该应用已在申请许可证时提交给美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）。这些监管机构的代表在现场检查期间专门审查了这项新的应用，并随后批准了产品和这项应用。目前，NIR 方法已作为一种主要的在线方法实施，以实时控制干燥终点（低于不大于 1.2%w/w 的控制限），用于商业化生产批次的已批准的固体口服药物。该过程内方法的实施允许实时控制，包括减少操作时间和劳动力；样品处理和废物产生；以及由于在该阶段提高了中间产品的一致性，进一步降低了对产品质量的风险。迄今为止，这部分制造过程已实现约 10%的能源效率和操作时间节省。
